PROJECT SUMMARY/ABSTRACT We propose to explore a new mechanism of ionizing radiation detection for positron emission tomography (PET) using the modulation of optical properties instead of scintillation, with the ultimate goal to achieve less than 10 picosecond (ps) annihilation photon pair coincidence time resolution, which is an order of magnitude better than possible with state-of-the-art scintillation based PET detectors. PET is a non-invasive imaging technology used every day throughout the world that enables visualization and quantification of the molecular signatures of disease in living subjects in the clinic as well as in biological research. A PET study comprises the collection of millions of annihilation photon pairs emitted from a positron-emitting radionuclide-labeled contrast agent injected into the patient. The two-photon hits are recorded by the system detectors and used to reconstruct a 3D image volume that represents the tracer biodistribution. If successful, the proposed < 10 ps coincidence time resolution would represent a tremendous paradigm shift for PET as it would drastically change the way a PET system operates. The resulting remarkable time-of-flight (ToF) capability will bring substantial signal amplification over existing systems. The enormous image signal-to-noise ratio (SNR) boost can be exploited to greatly enhance lesion detection, for example, for lesions with low contrast-to-background ratio; significantly reduce both patient injected dose and patient scan duration, potentially opening new clinical and research roles for which PET currently has no involvement at all; or pave the way for completely new PET system designs with greatly improved spatial resolution. In previous studies performed, we have shown that ionizing radiation can modulate optical properties, for example, the refractive index, of a detector material. We have found that the modulation signal amplitude is linearly dependent on both the event detection rate and average photon energy. In this project, we will work on further exploring mechanisms of optical property modulation to detect individual 511 keV photon interactions, and study the timing properties of this proposed detection concept with the goal to achieve < 10 ps coincidence time resolution. We first propose to achieve the detection of individual 511 keV photons using the mechanism of optical property modulation by developing novel methods to amplify the modulation signal and detection systems with significantly improved sensitivity. Then we plan to study the intrinsic timing properties of the optical property modulation process and explore methods to achieve < 10 ps coincidence time resolution for coincident 511 keV photon interactions. For the final aim, we will learn how to use this new mechanism of ionizing radiation detection to build a practical, ?tileable? ToF-PET detection element. This is an exciting multi-disciplinary project that borrows ideas from the field of modern optics with a goal of enabling substantial improvements in ToF-PET performance to drive important advances in the study and clinical management of disease.